SYSTEMIC D-AMPHETAMINE ADMINISTRATION CAUSES A REDUCTION OF KYNURENICACID LEVELS IN RAT-BRAIN

Tissue; levels of the endogenous excitatory amino acid receptor antago nist kynurenic acid (KYNA) and of its bioprecursor L-kynurenine were m easured in rats of different ages after d-amphetamine administration. In adult animals, extracellular KYNA concentrations were also determin ed in vivo by hippocampal microdialysis. In the adult brain, d-ampheta mine caused a transient, dose-dependent decrease in tissue content and extracellular levels of KYNA, reaching a nadir of approximately 70% o f control values after 1 h at 5 mg/kg. Quantitatively similar decremen ts were observed in four different brain regions. Seven, 14 and 28-day -old pups were particularly sensitive to the drug, showing a reduction in forebrain KYNA levels to 25%, 40% and 35% of control values, respe ctively, 1 h after the administration of 5 mg/kg d-amphetamine. Notabl y, no changes in brain L-kynurenine levels and in liver L-kynurenine a nd KYNA concentrations were found after d-amphetamine administration. Thus, endogenous monoamines released by d-amphetamine may interfere wi th the transamination of L-kynurenine to KYNA specifically in the brai n. These results suggest that d-amphetamine increases excitatory amino acid receptor function temporarily by reducing the levels of endogeno us KYNA. (C) 1998 Elsevier Science B.V. All rights reserved.